tbuckley/cabot-search huggingface dataset:
<scp>Anti‐CD3</scp> inhibits circulatory and tissue‐resident memory <scp>CD4</scp> T cells that drive asthma exacerbations in mice
Authors: Gurupreet S. Sethi, Donald T. Gracias, Rinkesh K. Gupta, Daniel Carr, Haruka Miki, Ricardo Da Silva Antunes, Michael Croft
Journal: Allergy (2023)

Exacerbations of asthma are thought to be strongly dependent on reactivation of allergen-induced lung tissue-resident and circulatory memory CD4 T cells. Strategies that broadly inhibit multiple T cell populations might then be useful to limit asthma. Accordingly, we tested whether targeting CD3 during exposure to inhaled allergen could prevent the accumulation of lung-localized effector memory CD4 T cells and block exacerbations of asthmatic inflammation.House dust mite-sensitized and repetitively challenged BL/6 mice were transiently treated therapeutically with F(ab')2 anti-CD3ε and memory T cell responses and lung inflammation were assessed. PBMCs from HDM-allergic donors were examined for the effect of anti-CD3 on expansion of allergen-reactive T cells.Allergen-sensitized mice undergoing exacerbations of asthma were protected from lung inflammation by transient therapeutic treatment with F(ab')2 anti-CD3. Regardless of whether sensitized mice underwent a secondary or tertiary recall response to inhaled allergen, anti-CD3 inhibited all phenotypes of effector memory CD4 T cells in the lung tissue and lung vasculature by 80%-90%, including those derived from tissue-resident and circulatory memory T cells. This did not depend on Treg cells suggesting it was primarily a blocking effect on memory T cell signaling. Correspondingly, anti-CD3 also strongly inhibited proliferation of human allergen-reactive memory CD4 T cells from allergic individuals. In contrast, the number of surviving tissue-resident memory CD4 T cells that were maintained in the lungs at later times was not robustly reduced by anti-CD3.Anti-CD3 F(ab')2 administration at the time of allergen exposure represents a viable strategy for limiting the immediate activity of allergen-responding memory T cells and asthma exacerbations.
Endothelial HDAC1-ZEB2-NuRD Complex Drives Aortic Aneurysm and Dissection Through Regulation of Protein S-Sulfhydration
Authors: Shanshan Luo, Chuiyu Kong, Shuang Zhao, Xin Tang, Yu Wang, Xuechun Zhou, Rui Li, Xingeng Liu, Xinlong Tang, Shixiu Sun, Wei Xie, Zhi-Ren Zhang, Qing Jing, Aihua Gu, Feng Chen, Dongjin Wang, Hong Wang, Yi Han, Liping Xie, Yong Ji
Journal: Circulation (2023)

Aortic aneurysm and aortic dissection (AAD) are life-threatening vascular diseases, with endothelium being the primary target for AAD treatment. Protein S-sulfhydration is a newly discovered posttranslational modification whose role in AAD has not yet been defined. This study aims to investigate whether protein S-sulfhydration in the endothelium regulates AAD and its underlying mechanism.Protein S-sulfhydration in endothelial cells (ECs) during AAD was detected and hub genes regulating homeostasis of the endothelium were identified. Clinical data of patients with AAD and healthy controls were collected, and the level of the cystathionine γ lyase (CSE)/hydrogen sulfide (H2S) system in plasma and aortic tissue were determined. Mice with EC-specific CSE deletion or overexpression were generated, and the progression of AAD was determined. Unbiased proteomics and coimmunoprecipitation combined with mass spectrometry analysis were conducted to determine the upstream regulators of the CSE/H2S system and the findings were confirmed in transgenic mice.Higher plasma H2S levels were associated with a lower risk of AAD, after adjustment for common risk factors. CSE was reduced in the endothelium of AAD mouse and aorta of patients with AAD. Protein S-sulfhydration was reduced in the endothelium during AAD and protein disulfide isomerase (PDI) was the main target. S-sulfhydration of PDI at Cys343 and Cys400 enhanced PDI activity and mitigated endoplasmic reticulum stress. EC-specific CSE deletion was exacerbated, and EC-specific overexpression of CSE alleviated the progression of AAD through regulating the S-sulfhydration of PDI. ZEB2 (zinc finger E-box binding homeobox 2) recruited the HDAC1-NuRD complex (histone deacetylase 1-nucleosome remodeling and deacetylase) to repress the transcription of CTH, the gene encoding CSE, and inhibited PDI S-sulfhydration. EC-specific HDAC1 deletion increased PDI S-sulfhydration and alleviated AAD. Increasing PDI S-sulfhydration with the H2S donor GYY4137 or pharmacologically inhibiting HDAC1 activity with entinostat alleviated the progression of AAD.Decreased plasma H2S levels are associated with an increased risk of aortic dissection. The endothelial ZEB2-HDAC1-NuRD complex transcriptionally represses CTH, impairs PDI S-sulfhydration, and drives AAD. The regulation of this pathway effectively prevents AAD progression.
Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant
Authors: Susan E. Prockop, Aisha Hasan, Ekaterina Doubrovina, Parastoo B. Dahi, Irene Rodriguez-Sanchez, Michael Curry, Audrey Mauguen, Genovefa A. Papanicolaou, Yiqi Su, JinJuan Yao, Maria Arcila, Farid Boulad, Hugo Castro-Malaspina, Christina Cho, Kevin J. Curran, Sergio Giralt, Nancy A. Kernan, Guenther Koehne, Ann Jakubowski, Esperanza Papadopoulos, Miguel-Angel Perales, Ioannis Politikos, Keith Price, Annamalai Selvakumar, Craig S. Sauter, Roni Tamari, Teresa Vizconde, James W. Young, Richard J. O’Reilly
Journal: Journal of Clinical Investigation (2023)

BACKGROUND. Refractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT).
Risk Factors Associated With Post−COVID-19 Condition
Authors: Vasiliki Tsampasian, Hussein Elghazaly, Rahul Chattopadhyay, Maciej Debski, Thin Kyi Phyu Naing, Pankaj Garg, Allan Clark, Eleana Ntatsaki, Vassilios S. Vassiliou
Journal: JAMA Internal Medicine (2023)

Post-COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support.To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC.Medline and Embase databases were systematically searched from inception to December 5, 2022.The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients.Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023.The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19.The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76).This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination.PROSPERO Identifier: CRD42022381002.
FLASH Radiotherapy in a Value-Based Health Care Environment—Reply
Authors: Anthony E. Mascia, Emily C. Daugherty, John C. Breneman
Journal: JAMA Oncology (2023)

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Concordance and Discrepancies Among 5 Creatinine-Based Equations for Assessing Estimated Glomerular Filtration Rate in Older Adults
Authors: Giorgi Beridze, Davide L. Vetrano, Alessandra Marengoni, Lu Dai, Juan-Jesús Carrero, Amaia Calderón-Larrañaga
Journal: JAMA Network Open (2023)

Importance There is uncertainty as to which estimated glomerular filtration rate (eGFR) equation should be used among older adults. Objective To compare the 5 most commonly used creatinine-based eGFR equations in older adults, quantifying the concordance among the equations, comparing their discriminative capacity in regards to 15-year mortality, and identifying sources of potential discrepancies. Design, Setting, and Participants This cohort study used data from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal study of adults aged 60 years or older in Sweden. Participants were recruited between 2001 and 2004 and followed up for mortality until December 2016. Participants missing creatinine values were excluded. Data were originally analyzed March through July 2022, and were rerun in January 2023. Exposures Five creatinine-based equations were considered: Modification of Diet in Renal Disease (MDRD), 2009 Chronic Kidney Disease Epidemiological Collaboration (CKD-EPI), Revised Lund-Malmö (RLM), Berlin Initiative Study (BIS), and European Kidney Function Consortium (EKFC). Main Outcomes and Measures Concordance between equations was quantified using Cohen κ. Discriminative capacity for mortality was quantified using area under the receiver operating characteristic curve (AUC) and the Harrel C statistic. Calf circumference, body mass index (BMI), and age were explored as correlates of discrepancies. Results The study sample consisted of 3094 older adults (1972 [63.7%] female; median [IQR] age, 72 [66-81] years). Cohen κ between dyads of equations ranged from 0.42 to 0.91, with poorest concordance between MDRD and BIS, and best between RLM and EKFC. MDRD and CKD-EPI provided higher estimates of GFR compared with the other equations. The best mix of AUC and Harrel C statistic was observed for BIS (0.80 and 0.73, respectively); however, the prognostic accuracy for death decreased among those aged over 78 years and those with low calf circumference. Differences between equations were inconsistent across levels of calf circumference, BMI, and age. Conclusions and Relevance In this cohort study, we found that eGFR equations were not interchangeable when assessing kidney function. BIS outperformed other equations in predicting mortality; however, its discriminative capacity was reduced in subgroup analyses. Clinicians should consider these discrepancies when monitoring kidney function in old age.
A Tumor-suppressive Molecular Axis EP300/circRERE/miR-6837-3p/MAVS Activates Type I IFN Pathway and Antitumor Immunity to Suppress Colorectal Cancer
Authors: Nan Ding, A-Bin You, Hu Yang, Guo-Sheng Hu, Chun-Ping Lai, Wen Liu, Feng Ye
Journal: Clinical Cancer Research (2023)

Abstract Purpose: The oncogenic role of circular RNAs (circRNA) has been well studied in cancers including colorectal cancer. However, tumor-suppressive circRNAs and the mechanism through which they exert their antitumor effects remain largely unknown. We aim to find out the critical tumor-suppressive circRNAs and their possibility to serve as gene therapy targets. Experimental Design: circRNA sequencing, gain-of-function and loss-of-function experiments, and transcriptomic analysis were performed to find tumor-suppressive and antitumor immunity effects of circRERE. Molecular biology experiments were conducted for mechanism exploration. Finally, we conducted adeno-associated virus (AAV) to deliver circRERE (circRERE-AAV) and evaluated circRERE-AAV alone and in combination with anti-PD-1 antibody in C57BL/6J mice bearing subcutaneous MC38 tumors. Results: circRERE is lowly expressed in colorectal cancer. Overexpression of circRERE inhibits the malignant behaviors of colorectal cancer in vitro and in vivo, while knockdown exhibits the opposite effects. The expression of circRERE is regulated by EP300, a histone acetyltransferase downregulated in colorectal cancer as well. Mechanistically, circRERE acts as a competitive endogenous RNA to sponge miR-6837-3p to upregulate MAVS expression, thereby activating type I IFN signaling and promoting antitumor immunity. Delivery of circRERE-AAV elicits significant antitumor effects, and combination treatment with circRERE-AAV and anti-PD-1 antibody exhibits synergistic effects on tumor growth in preclinical models of colorectal cancer. Conclusions: These results uncover modulatory axis constituting of EP300/circRERE/miR-6837-3p/MAVS and its essential roles in antitumor immunity, and demonstrate that circRERE-AAV might represent a new therapeutic avenue to prime immune responses and boost the effects of immunotherapy in clinic.
Trends of Randomized Clinical Trials Citing Prior Systematic Reviews, 2007-2021
Authors: Yuanxi Jia, Bingli Li, Zhirong Yang, Fuxiao Li, Ziyi Zhao, Chang Wei, Xuhao Yang, Qianyi Jin, Di Liu, Xin Wei, Jennifer Yost, Hans Lund, Jinling Tang, Karen A. Robinson
Journal: JAMA Network Open (2023)

Systematic reviews can help to justify a new randomized clinical trial (RCT), inform its design, and interpret its results in the context of prior evidence.
TMEM16E regulates endothelial cell procoagulant activity and thrombosis
Authors: Alec A. Schmaier, Papa F. Anderson, Siyu M. Chen, Emale El-Darzi, Ivan Aivasovsky, Milan P. Kaushik, Kelsey D. Sack, H. Criss Hartzell, Samir M. Parikh, Robert Flaumenhaft, Sol Schulman
Journal: Journal of Clinical Investigation (2023)

Endothelial cells (ECs) normally form an anticoagulant surface under physiological conditions, but switch to support coagulation following pathogenic stimuli. This switch promotes thrombotic cardiovascular disease. To generate thrombin at physiologic rates, coagulation proteins assemble on a membrane containing anionic phospholipid, most notably phosphatidylserine (PS). PS can be rapidly externalized to the outer cell membrane leaflet by phospholipid "scramblases," such as TMEM16F. TMEM16F-dependent PS externalization is well characterized in platelets. In contrast, how ECs externalize phospholipids to support coagulation is not understood. We employed a focused genetic screen to evaluate the contribution of transmembrane phospholipid transport on EC procoagulant activity. We identified 2 TMEM16 family members, TMEM16F and its closest paralog, TMEM16E, which were both required to support coagulation on ECs via PS externalization. Applying an intravital laser-injury model of thrombosis, we observed, unexpectedly, that PS externalization was concentrated at the vessel wall, not on platelets. TMEM16E-null mice demonstrated reduced vessel-wall-dependent fibrin formation. The TMEM16 inhibitor benzbromarone prevented PS externalization and EC procoagulant activity and protected mice from thrombosis without increasing bleeding following tail transection. These findings indicate the activated endothelial surface is a source of procoagulant phospholipid contributing to thrombus formation. TMEM16 phospholipid scramblases may be a therapeutic target for thrombotic cardiovascular disease.
Phase II study of nivolumab and salvage nivolumab/ipilimumab in treatment-naïve patients with advanced non-clear cell renal cell carcinoma (HCRN GU16-260-Cohort B)
Authors: Michael B Atkins, Opeyemi A Jegede, Naomi B Haas, David F McDermott, Mehmet A Bilen, Mark Stein, Jeffrey A Sosman, Robert Alter, Elizabeth R Plimack, Moshe C Ornstein, Michael Hurwitz, David J Peace, Sabina Signoretti, Thomas Denize, Alessia Cimadamore, Catherine J Wu, David Braun, David Einstein, Paul J Catalano, Hans Hammers
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background To determine the efficacy and toxicity of nivolumab monotherapy in treatment-naïve patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy. Methods Eligible patients with treatment-naïve nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were required to submit tissue from a metastatic lesion obtained within 12 months prior to study entry and prior to Part B for correlative studies. Results 35 patients with nccRCC were enrolled: 19 (54%) had papillary, 6 (17%) had chromophobe and 10 (29%) had unclassified histology. At median follow-up of 22.9 months, RECIST-defined objective response rate (ORR) was 5 of 35 (14.3% 95% CI 4.8% to 30.3%) (complete response (CR) 2 (5.7%) and partial response (PR) 3 (8.6%)). ORR by histology was: papillary—1/19 (5%); chromophobe—1/6 (17%); and unclassified—3/10 (30%). Nine patients (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified and 1 papillary) responding. ORR was 0/18, 3/11 (27%) and 2/6 (33%) for patients with tumor progammed death ligand 1 (PD-L1) expression of &lt;5%, ≥5% or not measured, respectively. Median progression-free survival was 4.0 (2.7–4.3) months. Two of five responders have progressed. Thirty-two patients had PD or prolonged SD and therefore, were potentially eligible for salvage nivolumab/ipilimumab (Part B), but 15 patients did not enroll due to grade 2–3 toxicity (6) on nivolumab, symptomatic disease progression (5), or other reasons including no biopsy tissue (4). In the 17 Part B patients, there was one PR (6%) (unclassified/non-sarcomatoid). Grade &gt; 3 treatment-related adverse events were seen in 7/35 (20%) on nivolumab and 7/17 (41%) on salvage nivolumab/ipilimumab with one patient experiencing sudden death. Conclusions Nivolumab monotherapy has limited activity in treatment-naïve nccRCC with most responses (4 of 5) seen in patients with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivolumab studies. Salvage treatment with nivolumab/ipilimumab was provided in half of these patients with minimal activity. Trial registration number NCT03117309 .
Sex-Specific Neurodevelopmental Outcomes Among Offspring of Mothers With SARS-CoV-2 Infection During Pregnancy
Authors: Andrea G. Edlow, Victor M. Castro, Lydia L. Shook, Sebastien Haneuse, Anjali J. Kaimal, Roy H. Perlis
Journal: JAMA Network Open (2023)

Importance Prior studies using large registries have suggested a modest increase in risk for neurodevelopmental diagnoses among children of mothers with immune activation during pregnancy, and such risk may be sex-specific. Objective To determine whether in utero exposure to SARS-CoV-2 is associated with sex-specific risk for neurodevelopmental disorders up to 18 months after birth, compared with unexposed offspring born during or prior to the COVID-19 pandemic period. Design, Setting, and Participants This retrospective cohort study included the live offspring of all mothers who delivered between January 1 and December 31, 2018 (born and followed up before the COVID-19 pandemic), between March 1 and December 31, 2019 (born before and followed up during the COVID-19 pandemic), and between March 1, 2020, and May 31, 2021 (born and followed up during the COVID-19 pandemic). Offspring were born at any of 8 hospitals across 2 health systems in Massachusetts. Exposures Polymerase chain reaction evidence of maternal SARS-CoV-2 infection during pregnancy. Main Outcomes and Measures Electronic health record documentation of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnostic codes corresponding to neurodevelopmental disorders. Results The COVID-19 pandemic cohort included 18 355 live births (9399 boys [51.2%]), including 883 (4.8%) with maternal SARS-CoV-2 positivity during pregnancy. The cohort included 1809 Asian individuals (9.9%), 1635 Black individuals (8.9%), 12 718 White individuals (69.3%), and 1714 individuals (9.3%) who were of other race (American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, more than 1 race); 2617 individuals (14.3%) were of Hispanic ethnicity. Mean maternal age was 33.0 (IQR, 30.0-36.0) years. In adjusted regression models accounting for race, ethnicity, insurance status, hospital type (academic center vs community), maternal age, and preterm status, maternal SARS-CoV-2 positivity was associated with a statistically significant elevation in risk for neurodevelopmental diagnoses at 12 months among male offspring (adjusted OR, 1.94 [95% CI 1.12-3.17]; P = .01) but not female offspring (adjusted OR, 0.89 [95% CI, 0.39-1.76]; P = .77). Similar effects were identified using matched analyses in lieu of regression. At 18 months, more modest effects were observed in male offspring (adjusted OR, 1.42 [95% CI, 0.92-2.11]; P = .10). Conclusions and Relevance In this cohort study of offspring with SARS-CoV-2 exposure in utero, such exposure was associated with greater magnitude of risk for neurodevelopmental diagnoses among male offspring at 12 months following birth. As with prior studies of maternal infection, substantially larger cohorts and longer follow-up will be required to reliably estimate or refute risk.